PENEDIL 5 MG EXTENDED-RELEASE TABLETS

Israel - English - Ministry of Health

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Active ingredient:
FELODIPINE
Available from:
TEVA PHARMACEUTICAL INDUSTRIES LTD, ISRAEL
ATC code:
C08CA02
Pharmaceutical form:
TABLETS EXTENDED RELEASE
Composition:
FELODIPINE 5 MG
Administration route:
PER OS
Prescription type:
Required
Manufactured by:
TEVA PHARMACEUTICAL INDUSTRIES LTD, ISRAEL
Therapeutic group:
FELODIPINE
Therapeutic area:
FELODIPINE
Therapeutic indications:
Moderade to severe hypertension.Angina pectoris.
Authorization number:
053 13 26329 00
Authorization date:
2011-02-28

PENEDIL EXTENDED RELEASE, 31. 7. 2013, RH

םיחקורה תונקת יפל ןכרצל ןולע

)

םירישכת

(

משתה

"

ו

-

986

1

תה הפור

ק

וושמ

ת

ע יפ ל דבלב אפור םשרמ

לידנפ

®

לידנפ

®

לידנפ

®

2.5

מ

"

ג

5

מ

"

ג

10

מ

"

ג

תיהשומ תוליעפ םע תוילבט

בכרה

בכרה

עפ םע הילבט לכ תולי הליכמ תיהשומ

Felodipine 2.5 mg

ןיפידולפ

Felodipine 5 mg

ןיפידולפ

Felodipine 10 mg

ןיפידולפ

תמישרל םיליעפ יתלבה םירמוחה רישכתב

האר ףיעס

"

ףסונ עדימ

"

הפורתב שמתשת םרטב ופוס דע ןולעה תא ןויעב ארק

.

הפורתה לע יתיצמת עדימ ליכמ הז ןולע

שי םא תופסונ תולאש ךל

חקורה לא וא אפורה לא הנפ

הפורת ךתלחמב לופיטל המשרנ וז

.

םירחאל התוא ריבעת לא

.

םהל קיזהל הלולע איה םג ךל הארנ םא מ יכ יאופרה םבצ המוד

.

1

.

הפורתה תדעוימ המל

?

רישכתה ןיפידולפ ליכמ תכיישה הפורת איהש צובקל

ןדיס תולעת ימסוח םשב העודיה

תלעופ הפורתה

"

םדה ילכ תבחרהו תייפרה י

עייסמ ךכבו

דרוהל הזחב םיבאכה תעינמו הובגה םדה ץחל ת

הזח תקועת

angina pectoris

תיט יופרת הצובק

םינידיריפורדיהיד תרזגנמ ןדיס תולעת םסוח

תד עוימ הניא הפורתה םידליב שומישל ליגל תחתמ

18

.

2

.

הפורתב שומישה ינפל

םא רישכתב שמתשהל ןיא מ לבוס התא

:

ןוירהב ךניה רשאכ

יריה תננכתמ ןו

היביכרממ דחאל תושיגר

םינידיריפורדיהיד גוסמ תופורתל תושיגר

ןיפידולמא וא ןיפידפינ ןוגכ

הביצי יתלב הזח תקועתמ

(unstable angina)

בלב תורומח תויעבמ לבוס ךניה םא ןורחאה שדוחב בל ףקתהמ תלבס םא וא

בלה רירש וא בלה ימותסש לש הלחממ

(hypertrophic cardiomyopathy)

שמתשת לא לבוס ךניה םא הפורתב ינגוידרק קושמ

לגוסמ וניא בלה ובו רומח בצמ ףוגל תקפסמ תומכב םד קפסל

PENEDIL EXTENDED RELEASE, 31. 7. 2013, RH

מישב תועגונה תודחוימ תורהזא

ו

ב ש הפורת

רבעב תלבס םא וא לבו ס ךניה םא אפורל רפסל שי לופיטה תלחתה ינפל

תויתואירבה תויעבהמ תואבה

:

דבכב תויעב

בלב תויעב

ןוגכ

ריהמ בל קפוד רתוי

ו הובג םד ץחל

ךומנ וא

תופסונ תורהזא

יהשלכ הפורתל וא והשלכ ןוזמל שיגר ךניה םא

הפורתה תליטנ ינפל אפורל ךכ לע עידוהל ךילע

זוטקלל םישיגרה םישנא לצא היגרלאל םורגל לולעו זוטקל ליכמ רישכתה

חקו ל התא םא

,

תחקל םא וא

ל

הנורחא

,

וכ תורחא תופורת הנוזת יפסותו םשרמ אלל תופורת לל

,

רפס חקורל וא אפורל ךכ לע

.

חקול התא םא חקורה וא אפורה תא עדייל שי דחוימב

ןידיטמיס

סוקלואב לופיטל

ןיצימורתירא

םיילאירטקב םימוהיז דגנ הקיטויביטנא

לוזנוקוטק וא לוזנוקרטיא

םייתיירטיפ םימוהיזל

תופורת םיזנא ימסוח

HIV protease

ב לופיטל

AIDS

ריבנוטיר ןוגכ

ןיאוטינפ

ןיפזמאברק

ןוטיברבונפ

היספליפאל

הליפנה תלחמ

סומילורקט

דבכ וא הילכ תלתשה רחאל שומישל

ןיצחפמפיר

תפחשב לופיטל

םוטרופרפ םוקירפיה

(St John’s Wort)

הדרחו ןואכידב לופיטל יאופר חמצ

םיטרוטיברב

העגרהל

בפא ןיפריבנ וא ץנ רי

תלחמב לופיטל

AIDS)

ןירפרוו

ידל

םד לו

ןירופסולקיצ

רקיע שומישה

"

תינורגש םיקרפמ תקלדב לופיטל םגו םירבא ילתשומ י סיזאירוספ תלחמו

תחפס

ןוז מו הפורתה תליטנ

ירישכת לש םתלועפ ךרד לע עיפשהל לולע תוילוכשא ץימ גוסמ ם דנפ ןוגכ ןדיס תולעת ימסוח לי

ןמזב ןכל וז הפורתב לופיטה יהל ךילע תשמ ענמ

תוילוכשא ץימ תי

ןוירה

הפורתב שמתשהל ןיא ןוירהב ךניה רשאכ

ןויריה תננכתמ

הקספ האר

"

הפורתב שומישה ינפל

("

ןוויכמ רבועל קיזהל לולע לידנפש

הקנה

ה תליטנ םרט הקינמ תא םא אפורל עידוהל שי הפורת

םי דליב שומיש

פורת םידליב שומישל תדעוימ הניא וז ה ליגל תחתמ

הגיהנ תונוכמב שו מישו

םוגפל לולע וז הפורתב שומישה וא הגיהנה רשוכב תונכוסמ תונוכמ תלעפה

תרוחרחס שח ךניהו הדימב תונוכמ ליעפהל וא גוהנל ןיא הפורתה תליטנ רחאל

3

.

הפורתב שמתשת דציכ

?

ה יפל הפורתב שמתשהל שי דימת אפורה תוארו

חוטב ךניא םא חקורה וא אפורה םע קודבל ךילע

דבלב אפורה ידי לע ועבקי לופיטה ןפואו ןונימה

םימ םע התומלשב הילבטה תא עולבל שי

תוצחל ןיא

קסרל הילבטה תא סועלל וא

אוה ללכ ךרדב לבוקמה ןונימה

םד ץחל רתי

)

םירגובמ

(

לש תחא הילבט

"

רקובב ג

PENEDIL EXTENDED RELEASE, 31. 7. 2013, RH

אפורה לש יתלחתה ןונימ לש ןתמ לוקשי

"

לעה לוקשי אפורה תא ל ןונימה

"

םויל ג

הזח תקועת

angina pectoris

)

םירגובמ

(

לש תחא הילבט

"

רקובב ג

ל ןונימה תא תולעהל לוקשי אפורה

"

םויל ג

םישישק

)

לעמ

65

(

םד ץחל רתיב לופיטל

תחא הילבט אוה לבוקמה ןונימה לש

"

רקובב ג

דיפקהל שי םירגובמ םילוחב רתויב ךומנה ןונימה ןתמ לע לופיטל יתלחתה

דבכה דוקפיתב יוקיל םע םילוח

ךומנ ןונימ ןתמ לוקשי אפורה רתוי לידנפ לש

תצלמומה הנמה לע רובעל ןיא

.

םידליב שומישל תדעוימ הניא הפורתה ליגל תחתמ

18

.

תלטנ םא

הפורתה ןמ רתי תנמ

,

הפורתה ןמ דלי עלב םא ןא

,

תיב לש ןוימ רדחל וא אפורל דימ תונפל שי הפורתה תזירא תא איבהלו םילוח

הפורתה תא לו טיל תחכש םא

שורדה ןמזב וז הפורת לוטיל תחכש םא

הלופכ הנמ לוטיל ןיא

ץעוויהו ליגרה ןמזב האבה הנמה תא חק אפורב

די לע ץלמוהש יפכ לופיטב דימתהל שי

אפורה

ךתואירב בצמב רופיש לח םא םג

לופיטה קיספהל ןיא תוצעייתה אלל הפורתב המידקמ חקורה וא אפורה םע

לו פיטה תחלצהל עייסל לכות דציכ

?

ךשוחב תופורת לוטיל ןיא

הנמהו תיוותה קודב םעפ לכב הפורת לטונ ךניהש

ךניה םא םייפקשמ בכרה םהל קוקז

ב תופסונ תולאש ךל שי םא הפורתב שומישל עגונ

חקורב וא אפורב ץעוויה

4

.

יאוול תועפות

הפורת לכל ומכ

שומישה רישכתב םישמתשמהמ קלחב יאוול תועפותל םורגל לולע

ארקמל להבית לא יאוולה תועפות תמישר

ןהמ תחא ףאמ לובסת אלו ןכתי

םא די מ אפורל תונפלו לופיטה קיספהל שי ה תועפותמ תחאב שח ךניה תואבה יאוול

:

וב תרוחרחסו הזחב םיבאכ

תינמז

תיגרלא הבוגת ךלצא החתפתה םא

םישוג לולכל םילולע םינמיס

םינפב תוחיפנ וא רועב

םייתפשב

הפב

ןורגב וא ןושלב

ןונ ימה תאלעה רחאל וא לופיטה תליחתב תואבה תועפותה תא שוחל לולע ךניה

הקמסה

שאר יבאכ

וא ריהמ רתוי בל קפוד קזח קפוד

תופייע וא תרוחרחס לש השגרה

תורחא יא וול תועפות שחרתהל תולולעה

:

דואמ תוחיכש יאוול תועפות

)

מ רתוי לע תועיפשמ

1

ךותמ

10

םילפוטמ

(

תוחיפנ םיילגרב םיילוסרקבו

תוחיכש יאוול תועפות

)

מ תוחפ לע תועיפשמ

1

ךותמ

10

םילפוטמ

(

שאר יבאכ

רועב הקמסה

PENEDIL EXTENDED RELEASE, 31. 7. 2013, RH

ול תועפות תוחיכש יתלב יאו

)

מ תוחפ לע תועיפשמ

1

ךותמ

100

םילפוטמ

(

ריהמ רתוי בל קפוד

קזח בל קפוד

היצטיפלפ

םיידיהו םיילגרה תועבצאב רורקיד תשוחת

ןטב באכ

הליחב

ילוח תשגרה

החירפ

דוריג

תרוחרחס

תופייע

תרוחרחס וא ןופלע תשגרהב אטבתמה ךומנ םד ץחל

תורידנ יאוול תועפות

)

מ

מ תוחפ לע תועיפש

1

ךותמ

1,000

םישנא

(

ןופלע

ילוח תשגרה

םיקרפמ יבאכ

םירירש יבאכ

הפקז לבקל תלוכי יא

תונוא ןיא

םישוגו החירפ

רועב

דואמ תורידנ יאוול תועפות

)

מ תוחפ לע תועיפשמ

1

ךותמ

10,000

םישנא

(

םייכינחב תוחיפנ

נ םייכינחמ לבוס ךניהו הדימב רימחהל לולע בצמה הליחתכלמ תוחופ

ןתינ ע וז העפות עונמל

"

םיינישהו הפה תנייגיה לע הרימש י

קידב תו דבכ ידוקפת לש תוניקת אל םד

רועב תקלד

שמשה רואל הפישחב שיגר רוע

תופוכת םיתיעל ןתש ןתמ

םויה ךשמב ללכ ךרדב

תיגרלא הבוגת

םינפב תוחיפנ ןוגכ רתי תושיגר

םייתפשב

הפב

רגב וא ןושלב ןו

םוח

הרימחמ יאוולה תועפותמ תחא םא

,

ןולעב הרכזוה אלש יאוול תעפותמ לבוס התא רשאכ וא

,

ךילע אפורה םע ץעייתהל דימ

.

5

.

הפורתה תא ןסחאל ךיא

הלערה ענמ

שיהל ץוחמ רוגס םוקמב רומשל שי תרחא הפורת לכו וז הפורת

ו םידלי לש םדי

וא תוקונית

הלערה ענמת ךכ ידי לעו

רופמ הארוה אלל האקהל םורגת לא

אפורהמ ת

הגופתה ךיראת ירחא הפורתב שמתשהל ןיא

Expiry date

הזיראה יבג לע עיפומה

הגופתה ךיראת שדוח ותוא לש ןורחאה םויל סחייתמ

שי ןסחאל שבי םוקמב

תחתמ

הפשאל וא בויבל תופורת ךילשהל ןיא

רת דימשהל דציכ חקורה תא לאש שומישב ןניא תופו

ולא םיעצמא הביבסה לע רומשל ורזעי

6

.

ףסונ עדימ

םג הליכמ הפורתה לי עפה רמוחה לע ףסונ

:

םיליעפ יתלב םיביכרמ

:

:::

droxypropyl methylcellulose, aluminium silicate, lactose, povidone (only in Penedil 5 & 10 mg

tablets), hydroxypropyl cellulose (only in Penedil 2.5 mg tablets), polyoxyl 40 hydrogenated castor

oil,

sodium

stearyl

fumarate,

microcrystalline

cellulose,

polyethylene

glycol

6000,

titanium

dioxide, carnauba wax, iron oxide yellow, propyl gallate, red-brown ferric oxide (only in Penedil 5

& 10 mg tablets).

PENEDIL EXTENDED RELEASE, 31. 7. 2013, RH

לידנפ

2.5

מ

"

ג

הליכמ הילבט לכ

:

28

מ

"

ו זוטקל ג

-

0.23

מ

"

ןרתנ ג

.

לידנפ

5

מ

"

ג

:

הליכמ הילבט לכ

:

56

מ

"

ו זוטקל ג

-

0.50

מ

"

ןרתנ ג

.

לידנפ

10

מ

"

ג

הליכמ הילבט לכ

:

56

מ

"

ו זוטקל ג

-

0.52

מ

"

ןרתנ ג

.

הזיראה ןכ ות המו הפורתה תיארנ דציכ

"

בט תובוהצ תויל

תולוגע

תורומק

"

תודורו תוילבט תורומקו תולוגע

"

םודא עבצב תוילבט

תורומקו תולוגע םוח

םו שירה לעב

עב תויטבצמרפ תוישעת עבט

"

"

3190

חתפ

הוקת

ותבותכו ןרציה םש

עב תויטבצמרפ תוישעת עבט

"

"

3190

חתפ

הוקת

ע רשואו קדבנ הז ןולע

"

תואירבה דרשמ

ילוי

2013

רפסמ

תואירבה דרשמב יתכלממה תופורתה סקנפב הפורתה םושיר

"

101 52 28338 00

"

053 13 26329 00

"

053 12 26330 00

האירקה תלקהלו תוטשפה םשל

רכז ןושלב חסונ הז ןולע

תאז ףא לע

ימה ינש ינבל תדעוימ הפורתה םינ

PENEDIL 31. 7. 2013, RH

"

ע עבקנ הז ןולע טמרופ

"

רשואו קדבנ ונכותו תואירבה דרשמ י

."

רשואמ ןולע

ילוי

2013

“This leaflet form

at has been determined by the Ministry of Health and the content thereof has been checked

and approved.” Date of approval: July 2013

SUMMARY OF PRODUCT CHARACTERISTICS

1.

NAME OF THE MEDICINAL PRODUCT

Penedil 2.5mg extended-release tablets

Penedil 5 mg extended-release tablets

Penedil 10 mg extended-release tablets

2.

QUALITATIVE AND QUANTITATIVE COMPOSITION

1 extended-release tablet contains:

Felodipine 2.5 mg, 5 mg or 10 mg.

For excipients, see section 6.1.

3.

PHARMACEUTICAL FORM

Extended

-

release tablets

Appearance

2.5 mg:

yellow, circular, biconvex film coated , tablets plain on both sides.

5 mg:

pink, circular, biconvex coated tablets.

10 mg:

red-brown, circular biconvex film coated tablets.

4.

CLINICAL PARTICULARS

4.1 Therapeutic indications

Hypertension, angina pectoris.

4.2 Posology and method of administration

For oral administration.

The tablets should be taken in the morning and be swallowed with water. In order to keep

the prolonged release properties, the tablets must not be divided, chewed or crushed. The

tablets can be administered without food or following a light meal not rich in fat or

carbohydrate.

Hypertension

Adults (including elderly) The dose should be adjusted to the individual requirements of

the patient. The recommended starting dose is 5mg once daily. If necessary the dose may

be further increased or another antihypertensive agent added. The usual maintenance dose

is 5 - 10 mg once daily. Doses higher than 20 mg daily are not usually needed. For dose

titration purposes a 2.5 mg tablet is available. In elderly patients an initial treatment with

2.5 mg daily should be considered.

Angina pectoris

Adults The dose should be adjusted individually. Treatment should be started with 5mg

once daily and if needed be increased to 10mg once daily.

PENEDIL 31. 7. 2013, RH

Children The safety and efficacy of Penedil in children has not been established.

Penedil can be used in combination with

-blockers, ACE inhibitors or diuretics. The

effects on blood pressure are likely to be additive and combination therapy will usually

enhance the antihypertensive effect. Care should be taken to avoid hypotension.

Hepatic Impairment

Patients

with

impaired

hepatic

function

have

elevated

plasma

concentrations

felodipine and may respond to lower doses (see section 4.4 and section 5.2).

Renal Impairment

Dose

adjustment

needed

patients

with

impaired

renal

function.

pharmacokinetics are not significantly affected in patients with impaired renal function.

4.3 Contra-indications

Unstable angina pectoris.

Pregnancy.

Patient with a previous allergic reaction to Penedil or other dihydropyridines because of the

theoretical risk of cross-reactivity.

Penedil

should

used

patients

with

clinically

significant

aortic

stenosis,

haemodynamically

significant

cardiac

valvular

obstruction,

dynamic

cardiac

outflow

obstruction uncompensated heart failure, and during or within one month of an acute

myocardial infarction.

As with other calcium channel blockers, Penedil should be discontinued in patients who

develop cardiogenic shock.

4.4 Special warnings and precautions for use

As with other vasodilators, Penedil may precipitate significant hypotension with subsequent

tachycardia. This may lead to myocardial ischaemia in susceptible patients.

There

evidence

that

Penedil

useful

secondary

prevention

myocardial

infarction.

The efficacy and safety of Penedil in the treatment of malignant hypertension has not been

studied.

Penedil should be used with caution in patients with severe left ventricular dysfunction.

Mild

gingival

enlargement

been

reported

patients

with

pronounced

gingivitis/periodontitis. The enlargement can be avoided or reversed by careful dental

hygiene.

Felodipine is cleared by the liver. Consequently higher therapeutic concentrations and

response can be expected in patients with clearly reduced liver function (see also section

4.2).

PENEDIL 31. 7. 2013, RH

Penedil contains lactose and patients with hereditary galactose intolerance, the Lapp lactase

deficiency or glucose-galactose malabsorption should not take this product.

4.5 Interaction with other medicinal products and other forms of interaction

Enzyme interactions

Felodipine is metabolized in the liver by cytochrome P450 3A4 (CYP3A4). Enzyme

inhibiting and enzyme inducing substances of cytochrome P450 isoenzyme 3A4 may exert

an influence on the plasma level of felodipine.

Interactions leading to increased plasma concentrations of felodipine

Enzyme inhibitors of the cytochrome P450 3A4 system have been shown to cause an

increase in felodipine plasma concentrations such as cimetidine, erythromycin, itraconazole,

ketoconazole and anti HIV/protease inhibitors (e.g. ritonavir) impair the elimination of

felodipine,

Penedil

dosage

need

reduced

when

drugs

given

concomitantly.

Interactions leading to decreased plasma concentrations of felodipine

Enzyme inducers of the cytochrome P450 3A4 system may cause a decrease in plasma

concentrations of felodipine such as phenytoin, carbamazepine, phenobarbital, rifampicin,

barbiturates, efavirenz, nevirapine and hypericum perforatum (St John’s wort). Higher than

normal Penedil doses may be required in patients taking these drugs.

Additional interactions

No dosage adjustment is required when Penedil is given concomitantly with digoxin.

The high degree of plasma protein binding of felodipine does not appear to affect the

unbound fraction of other extensively plasma protein bound drugs such as warfarin.

Felodipine

increase

concentration

tacrolimus.

When

used

together,

tacrolimus serum concentration should be followed and the tacrolimus dose may need to be

adjusted.

Felodipine does not affect plasma concentrations of ciclosporin.

Grapefruit juice results in increased peak plasma levels and bioavailability possibly due to

an interaction with flavonoids in the fruit juice. This interaction has been seen with other

dihydropyridine calcium antagonists and represents a class effect. Therefore grapefruit juice

should not be taken together with Penedil tablets.

4.6 Fertility, pregnancy and lactation

Data on male and female fertility in patients are missing (see section 5.3).

Pregnancy

Felodipine should not be given during pregnancy.

In a study on fertility and general reproductive performance in rats, a prolongation of

parturition resulting in difficult labour, increased foetal deaths and early postnatal deaths

were observed in the medium-and high-dose groups. Reproductive studies in rabbits have

shown a dose-related reversible enlargement of the mammary glands of the parent animals

and dose-related digital abnormalities in the foetuses when felodipine was administered

during stages of early foetal development.

PENEDIL 31. 7. 2013, RH

Lactation

Felodipine has been detected in breast milk; When taken in therapeutic doses by the nursing

mother it is, however, not likely to affect the infant.

4.7 Effects on ability to drive and use machines

Patients should know how they react to felodipine before they drive or use machines

because occasionally dizziness or fatigue may occur.

4.8 Undesirable effects

Like

other

arteriolar

dilators,

felodipine

cause

flushing,

headache,

palpitations,

dizziness and fatigue. Most of these reactions are dose-dependent and appear at the start of

treatment or after a dose increase. Should such reactions occur, they are usually transient

and diminish with time.

As with other dihydropyridines, dose-dependent ankle swelling can occur in patients treated

with felodipine. This results from precapillary vasodilatation and is not related to any

generalised fluid retention. Experience from clinical trials has shown that 2 % of patients

interrupted treatment due to ankle swelling.

As with other calcium antagonists, mild gingival enlargement has been reported in patients

with pronounced gingivitis/periodontitis. The enlargement can be avoided or reversed by

careful dental hygiene.

As with other dihydropyridines, aggravation of angina has been reported in a small number

of individuals especially after starting treatment. This is more likely to happen in patients

with symptomatic ischaemic heart disease.

The following adverse events have

been reported from clinical trials and from Post

Marketing Surveillance. The following adverse events have been reported from clinical

trials and from Post Marketing Surveillance. The following definitions of frequencies are

used: Very common (≥1/10), common (≥1/100 and <1/10), uncommon (≥1/1000 and

<1/100), rare (≥1/10000 and <1/1000) and very rare (<1/10000).

System Organ class

Frequency

Adverse Drug Reaction

Nervous system disorders

Common

Uncommon

Headache

Dizziness, paraesthesia

Cardiac disorders

Uncommon

Tachycardia, palpitations

Vascular disorders

Common

Uncommon

Rare

Flush

Hypotension

Syncope

Gastrointestinal disorders

Uncommon

Rare

Very rare

Nausea, abdominal pain

Vomiting

Gingival hyperplasia, gingivitis

PENEDIL 31. 7. 2013, RH

System Organ class

Frequency

Adverse Drug Reaction

Hepatobiliary disorders

Very rare

Increased liver enzymes

Skin and subcutaneous tissue

disorders

Uncommon

Rare

Very rare

Rash, pruritus

Urticaria

Photosensitivity reactions,

leucocytoclastic vasculitis

Musculoskeletal and connective

tissue disorders

Rare

Arthralgia, myalgia

Renal and urinary disorders

Very rare

Pollakisuria

Reproductive system and breast

disorders

Rare

Impotence/sexual dysfunction

General disorders and

administration site conditions

Very common

Uncommon

Very rare

Peripheral oedema

Fatigue

Hypersensitivity reactions, e.g. angio-

oedema, fever

4.9 Overdose

Symptoms:

Overdosage

cause

excessive

peripheral

vasodilatation

with

marked

hypotension which may sometimes be accompanied by bradycardia.

Management: Activated charcoal, induction of vomiting or gastric lavage, if appropriate or

indicated. Severe hypotension should be treated symptomatically, with the patient placed

supine and the legs elevated. Bradycardia, if present, should be treated with atropine 0.5-

1mg i.v. If this is not sufficient, plasma volume should be increased by infusion of e.g.

glucose, saline or dextran. Sympathomimetic drugs with predominant effect on the α

adrenoceptor may be given e.g. metaraminol or phenylephrine if the above-mentioned

measures are insufficient.

5.

PHARMACOLOGICAL PROPERTIES

Pharmacotherapeutic group: Calcium antagonist. ATC code: C08C A02

5.1 Pharmacodynamic properties

Felodipine is a vascular selective calcium antagonist, which lowers arterial blood pressure

by decreasing peripheral vascular resistance. Due to the high degree of selectivity for

smooth muscle in the arterioles, felodipine in therapeutic doses has no direct effect on

cardiac contractility or conduction.

It can be used as monotherapy or in combination with other antihypertensive drugs, e.g.

-receptor

blockers,

diuretics

ACE-inhibitors,

order

achieve

increased

antihypertensive effect. Felodipine reduces both systolic and diastolic blood pressure and

can be used in isolated systolic hypertension. In a study of 12 patients, felodipine

maintained its antihypertensive effect during concomitant therapy with indomethacin.

Because there is no effect on venous smooth muscle or adrenergic vasomotor control,

felodipine is not associated with orthostatic hypotension.

PENEDIL 31. 7. 2013, RH

Felodipine has anti-anginal and anti-ischaemic effects due to improved myocardial oxygen

supply/demand balance. Coronary vascular resistance is decreased and coronary blood flow

as well as myocardial oxygen supply are increased by felodipine due to dilation of both

epicardial arteries and arterioles. Felodipine effectively counteracts coronary vasospasm.

The reduction in systemic blood pressure caused by felodipine leads to decreased left

ventricular afterload.

Felodipine improves exercise tolerance and reduces anginal attacks in patients with stable

effort induced angina pectoris. Both symptomatic and silent myocardial ischaemia are

reduced by felodipine in patients with vasospastic angina. Felodipine can be used as

monotherapy or in combination with

-receptor blockers in patients with stable angina

pectoris.

Felodipine possesses a mild natriuretic/diuretic effect and generalised fluid retention does

not occur.

Felodipine is well tolerated in patients with concomitant disease such as congestive heart

failure well-controlled on appropriate therapy, asthma and other obstructive pulmonary

diseases, diabetes, gout, hyperlipidemia impaired renal function, renal transplant recipients

and Raynaud's disease. Felodipine has no significant effect on blood glucose levels or lipid

profiles.

Haemodynamic effects: The primary haemodynamic effect of felodipine is a reduction of

total peripheral vascular resistance which leads to a decrease in blood pressure. These

effects are dose-dependent. In patients with mild to moderate essential hypertension, a

reduction in blood pressure usually occurs 2 hours after the first oral dose and lasts for at

least 24 hours with a trough/peak ratio usually above 50%.

Plasma concentration of felodipine and decrease in total peripheral resistance and blood

pressure are positively correlated.

Electrophysiological and other cardiac effects: Felodipine in therapeutic doses has no effect

on cardiac contractility or atrioventricular conduction or refractoriness.

Renal effects: Felodipine has a natriuretic and diuretic effect. Studies have shown that the

tubular reabsorption of filtered sodium is reduced. This counteracts the salt and water

retention observed for other vasodilators. Felodipine does not affect the daily potassium

excretion. The renal vascular resistance is decreased by felodipine. Normal glomerular

filtration rate is unchanged. In patients with impaired renal function glomerular filtration

rate may increase.

Felodipine is well tolerated in renal transplant recipients.

Site and mechanism of action: The predominant pharmacodynamic feature of felodipine is

its pronounced vascular versus myocardial selectivity. Myogenically active smooth muscles

in arterial resistance vessels are particularly sensitive to felodipine.

Felodipine inhibits electrical and contractile activity of vascular smooth muscle cells via an

effect on the calcium channels in the cell membrane.

PENEDIL 31. 7. 2013, RH

There is limited clinical trial experience of the use of felodipine in hypertensive paediatric

patients. In a randomised, double-blind, 3-week, parallel group study in children aged 6-16

years with primary hypertension, the antihypertensive effects of once daily felodipine 2.5

mg (n=33), 5 mg (n=33) and 10 mg (n=31) were compared with placebo (n=35). The study

failed to demonstrate the efficacy of felodipine in lowering blood pressure in children aged

6-16 years.

The long-term effects of felodipine on growth, puberty and general development have not

been studied. The long-term efficacy of felodipine as therapy in childhood to reduce

cardiovascular morbidity and mortality in adulthood has also not been established.

5.2 Pharmacokinetic properties

Absorption and distribution: Felodipine is completely absorbed from the gastrointestinal

tract after administration of felodipine extended release tablets.

The systemic availability of felodipine is approximately 15% in man and is independent of

dose in the therapeutic dose range.

With the extended-release tablets the absorption phase is prolonged. This results in even

felodipine plasma concentrations within the therapeutic range for 24 hours.

The plasma protein binding of felodipine is approximately 99%. It is bound predominantly

to the albumin fraction.

Elimination and metabolism: The average half-life of felodipine in the terminal phase is 25

hours. There is no significant accumulation during long-term treatment. Felodipine is

extensively metabolised in the liver by cytochrome P450 3A4 (CYP3A4) and all identified

metabolites are inactive. Elderly patients and patients with reduced liver function have an

average higher plasma concentration of felodipine than younger patients.

About 70% of a given dose is excreted as metabolites in the urine; the remaining fraction is

excreted in the faeces. Less than 0.5% of a dose is recovered unchanged in the urine.

The kinetics of felodipine are not changed in patients with renal impairment.

In a single dose (felodipine extended release 5 mg) pharmacokinetic study in twelve

children aged between 6 and 16 years (n=12) there was no apparent relationship between

age and AUC, C

or half-life of felodipine.

5.3 Preclinical safety data

Felodipine is a calcium antagonist and lowers arterial blood pressure by decreasing vascular

resistance. In general a reduction in blood pressure is evident 2 hours after the first oral dose

and at steady state lasts for at least 24 hours after dose.

Felodipine exhibits a high degree of selectivity for smooth muscles in the arterioles and in

therapeutic doses has no direct effect on cardiac contractility. Felodipine does not affect

venous smooth muscle and adrenergic vasomotor control.

Electrophysiological studies have shown that felodipine has no direct effect on conduction

in the specialised conducting system of the heart and no effect on the AV nodal refractories.

PENEDIL 31. 7. 2013, RH

Penedil possesses a mild natriuretic/diuretic effect and does not produce general fluid

retention, nor affect daily potassium excretion. Penedil is well tolerated in patients with

congestive heart failure.

6.

PHARMACEUTICAL PARTICULARS

6.1 List of Excipients

Penedil 2.5 mg extended-release tablets

Hydroxypropyl

methylcellulose,

aluminium

silicate,

lactose

anhydrous,

hydroxypropyl

cellulose, sodium stearyl fumarate, microcrystalline cellulose, polyoxyl

hydrogenated

castor oil, polyethylene glycol 6000, titanium dioxide, iron dioxide yellow, carnauba wax,

propyl gallate.

Lactose content:

28 mg per tablet.

Sodium content:

0.23 mg per tablet.

Penedil 5 mg or 10 mg extended-release tablets

Hydroxypropyl methylcellulose, aluminium silicate, lactose anhdrous, povidone, polyoxyl

hydrogenated

castor

oil.,

sodium

stearyl

fumarate,

microcrystalline

cellulose,

polyethylene glycol 6000, titanium dioxide, carnauba wax, propyl gallate, red-brown ferric

oxide, yellow ferric oxide.

Penedil 5 mg extended release tablets

Lactose content:

56 mg per tablet.

Sodium content:

0.50 mg per tablet.

Penedil 10mg extended release tablets

Lactose content:

56 mg

per tablet.

Sodium content:

0.52 mg per tablet

6.2

Special Precautions for Storage:

Store in a dry place below 25C.

Please refer to expiry date on the label and outer carton.

6.3 Registration Numbers:

Penedil 2.5 mg: 101 52 28338 00.

Penedil 5 mg: 053 13 26329 00.

Penedil 10 mg: 053 12 26330 00.

6.4 Presentation

Penedil 2.5 mg: 30 tablets

Penedil 5 mg: 30 tablets

Penedil 10 mg: 30 tablets

7.

MANUFACTURER

Teva Pharmaceutical Industries Ltd

P.O.Box 3190, Petach Tikva.

העדוה העדוה

לע לע

הרמחה הרמחה

(

(

עדימ עדימ

תוחיטב תוחיטב

ךיראת

____________

July 10, 2013

___

םש

רישכת

תילגנאב

PENEDIL Extended Release Tablets 2.5, 5, 10 mg

רפסמ

_םושיר

2.5

mg: 101 52 28338 00, 5mg: 053 13 26329 00

10

mg: 053 12 26330 00

םש

לעב

םושירה

Teva Pharmaceutical Industries Ltd., POBox 3190, Petach Tikva

ספוט

הז

דעוימ

טורפל

תורמחהה

דבלב

ןולעב ןולעב

אפור אפור תורמחהה

תושקובמה קרפ

ןולעב טסקט

יחכונ טסקט

שדח

Indication

contraindications

Penedil should not be used in

patients with clinically significant

aortic

stenosis,

uncompensated

heart failure, and during or within

month

myocardial

infarction.

Penedil should not be used in patients with

clinically

significant

aortic

stenosis,

haemodynamically significant cardiac valvular

obstruction, dynamic cardiac outflow obstruction

uncompensated heart failure, and during or

within one month of an acute myocardial

infarction.

Posology, dosage &

administration

Special Warnings and

Special Precautions

for Use

As with other vasodilators, Penedil may, in

rare

cases,

precipitate

significant

hypotension with tachycardia

As with other vasodilators, Penedil may, in rare cases,

precipitate

significant

hypotension

with

subsequent

tachycardia

Mild gingival enlargement has been reported in

patients with pronounced gingivitis/periodontitis.

The enlargement can be avoided or reversed by

careful dental hygiene.

Felodipine is cleared by the liver. Consequently

higher therapeutic concentrations and response

can be expected in patients with clearly reduced

liver function (see also section 4.2).

Penedil contains lactose and patients with

hereditary galactose intolerance, the Lapp lactase

deficiency or glucose-galactose malabsorption

should not take this product.

Undesirable effects

with

other

calcium

antagonists, felodipine can cause

flushing, headache, palpitations,

dizziness and fatigue may occur.

These

reactions

usually

transient and are most likely to

occur at the start of treatment or

after an increase in dosage.

As with other calcium antagonists

Like other arteriolar dilators As with other

calcium

antagonists,

felodipine

cause

flushing, headache, palpitations, dizziness and

fatigue may occur. Most of these reactions are

dose-dependent and appear at the start of

treatment or after a dose increase. Should such

reactions occur, they are usually transient and

diminish with time These reactions are usually

transient and are most likely to occur at the start

of treatment or after an increase in dosage.

ankle swelling, resulting from

precapillary

vasodilation,

occur.

degree

ankle

swelling is dose related.

patients

with

gingivitis/periodontitis,

mild

gingival enlargement has been

reported with Penedil, as with

other calcium antagonists. The

enlargement can be avoided or

reversed

careful

dental

hygiene.

As with other dihydropyridines,

aggravation of angina has been

reported in a small number of

individuals

especially

after

starting treatment. This is more

likely to happen in patients with

symptomatic

ischaemic

heart

disease.

following

adverse

events

have been reported from clinical

trials and from Post Marketing

Surveillance.

In the great majority of cases a

causal relationship between these

events

treatment

with

felodipine

been

established.

Skin:

very

rarely

leucocytoclastic vasculitis, rarely

- rash and/or pruritus, and isolated

cases of photosensitivity.

Musculoskeletal:

isolated

cases arthralgia and myalgia.

Psychiatric:

rarely

impotence/sexual dysfunction.

Central and peripheral nervous

system: headache, dizziness. In

isolated cases paraesthesia.

Gastrointestinal: very rarely -

gingivitis,

isolated

cases

abdominal pain, nausea, vomiting,

gum hyperplasia.

Hepatic:

isolated

cases

increased liver enzymes.

Urinary system:

very rarely

urinary frequency.

Cardiovascular:

rarely

tachycardia,

palpitations

syncope.

Vascular

(extracardiac):

peripheral oedema, flush.

Other: very rarely - fever, rarely

fatigue,

isolated

cases

hypersensitivity

reactions

e.g.

urticaria, angio-oedema.

As with other dihydropyridines, dose-dependent

ankle swelling can occur in patients treated with

felodipine.

This

results

from

precapillary

vasodilatation

related

generalised fluid retention. Experience from

clinical trials has shown that 2 % of patients

interrupted treatment due to ankle swelling.

As with other calcium antagonists, mild gingival

enlargement has been reported in patients with

pronounced

gingivitis/periodontitis.

enlargement can be avoided or reversed by

careful dental hygiene.

with

other

calcium

antagonists

ankle

swelling,

resulting

from

precapillary

vasodilation, may occur. The degree of ankle

swelling is dose related.

In patients with gingivitis/periodontitis, mild

gingival enlargement has been reported with

Penedil, as with other calcium antagonists. The

enlargement can be avoided or reversed by

careful dental hygiene.

As with other dihydropyridines, aggravation of

angina has been reported in a small number of

individuals especially after starting treatment.

This is more likely to happen in patients with

symptomatic ischaemic heart disease.

The following adverse events have been reported

from clinical trials and from Post Marketing

Surveillance. The following adverse events have

been reported from clinical trials and from Post

Marketing

Surveillance.

following

definitions

frequencies

used:

Very

common (≥1/10), common (≥1/100 and <1/10),

uncommon

(≥1/1000

<1/100),

rare

(≥1/10000

<1/1000)

very

rare

(<1/10000).

great

majority

cases

causal

relationship between these events and treatment

with felodipine has not been established.

System Organ

class

Frequency

Adverse Drug

Reaction

Nervous system

disorders

Common

Uncommon

Headache

Dizziness,

paraesthesia

Cardiac disorders

Uncommon

Tachycardia,

palpitations

Vascular

disorders

Common

Uncommon

Rare

Flush

Hypotension

Syncope

Gastrointestinal

disorders

Uncommon

Rare

Very rare

Nausea,

abdominal pain

Vomiting

Gingival

hyperplasia,

gingivitis

Hepatobiliary

disorders

Very rare

Increased liver

enzymes

Skin and

subcutaneous

tissue disorders

Uncommon

Rare

Very rare

Rash, pruritus

Urticaria

Photosensitivity

reactions,

leucocytoclastic

vasculitis

Musculoskeletal

and connective

tissue disorders

Rare

Arthralgia,

myalgia

Renal and urinary

Very rare

Pollakisuria

disorders

Reproductive

system and breast

disorders

Rare

Impotence/sexual

dysfunction

General disorders

and

administration

site conditions

Very common

Uncommon

Very rare

Peripheral oedema

Fatigue

Hypersensitivity

reactions, e.g.

angio-oedema,

fever

Skin: very rarely - leucocytoclastic vasculitis,

rarely - rash and/or pruritus, and isolated cases of

photosensitivity.

Musculoskeletal: in isolated cases arthralgia

and myalgia.

Psychiatric:

rarely

impotence/sexual

dysfunction.

Central

and

peripheral

nervous

system:

headache,

dizziness.

isolated

cases

paraesthesia.

Gastrointestinal: very rarely - gingivitis, in

isolated cases abdominal pain, nausea, vomiting,

gum hyperplasia.

Hepatic:

in isolated cases increased liver

enzymes.

Urinary system: very rarely urinary frequency.

Cardiovascular:

rarely

tachycardia,

palpitations and syncope.

Vascular (extracardiac): peripheral oedema,

flush.

Other: very rarely - fever, rarely - fatigue, in

isolated cases hypersensitivity reactions e.g.

urticaria, angio-oedema.

Interaction with

Other Medicaments

and Other Forms of

Interaction

Concomitant

administration

substances which interfere with

cytochrome

P450

enzyme system may affect plasma

concentrations

felodipine.

Enzyme

inhibitors

such

cimetidine,

erythromycin,

itraconazole

ketoconazole

impair

elimination

felodipine, and Penedil dosage

may need to be reduced when

drugs are given concomitantly.

Conversely,

powerful

enzyme

inducing agents such as some

anticonvulsants

(phenytoin,

carbamazepine,

phenobarbital)

increase

felodipine

elimination

higher

than

normal Penedil doses may be

required in patients taking the

drugs.

No dosage adjustment is required

when

Penedil

given

concomitantly with digoxin.

felodipine does not appear to

affect the unbound fraction of

other extensively plasma protein

bound drugs such as warfarin.

Felodipine

increase

concentration

tacrolimus.

When

used

together,

tacrolimus serum concentration

should

followed

tacrolimus dose may need to be

Enzyme interactions

Felodipine is metabolized in the liver by

cytochrome P450 3A4 (CYP3A4). Enzyme

inhibiting and enzyme inducing substances of

cytochrome P450 isoenzyme 3A4 may exert an

influence on the plasma level of felodipine.

Interactions

leading

increased

plasma

concentrations of felodipine

Enzyme inhibitors of the cytochrome P450 3A4

system have been shown to cause an increase in

felodipine

plasma

concentrations

such

cimetidine,

erythromycin,

itraconazole,

ketoconazole and anti HIV/protease inhibitors

(e.g.

ritonavir)

impair

elimination

felodipine, and Penedil dosage may need to be

reduced when drugs are given concomitantly.

Interactions

leading

decreased

plasma

concentrations of felodipine

Enzyme inducers of the cytochrome P450 3A4

system

cause

decrease

plasma

concentrations of felodipine such as phenytoin,

carbamazepine,

phenobarbital,

rifampicin,

barbiturates,

efavirenz,

nevirapine

hypericum perforatum (St John’s wort). Higher

than normal Penedil doses may be required in

patients taking these drugs.

Additional interactions

No dosage adjustment is required when Penedil

is given concomitantly with digoxin.

Concomitant administration of substances which

interfere with the cytochrome P450 3A4 enzyme

system may affect plasma concentrations of

adjusted.

felodipine. Enzyme inhibitors such as cimetidine,

erythromycin, itraconazole and ketoconazole

impair the elimination of felodipine, and Penedil

dosage may need to be reduced when drugs are

given concomitantly.

Conversely, powerful

enzyme

inducing

agents

such

some

anticonvulsants

(phenytoin,

carbamazepine,

phenobarbital)

increase

felodipine

elimination and higher than normal Penedil doses

may be required in patients taking the drugs.

No dosage adjustment is required when Penedil

is given concomitantly with digoxin.

The high degree of plasma protein binding of

felodipine does not appear to affect the unbound

fraction of other extensively plasma protein

bound drugs such as warfarin.

Felodipine may increase the concentration of

tacrolimus. When used together, the tacrolimus

serum concentration should be followed and the

tacrolimus dose may need to be adjusted.

Felodipine does not affect plasma concentrations

of ciclosporin.

Fertility, pregnancy

and Lactation

Lactation

Felodipine has been detected in

breast milk;., but it is unknown

whether it has harmful effects on

the new-born.

Data on male and female fertility in patients are

missing (see section 5.3).

Lactation

Felodipine has been detected in breast milk;

When taken in therapeutic doses by the nursing

mother it is, however, not likely to affect the

infant., but it is unknown whether it has harmful

effects on the new-born.

Effects on ability to

drive and use

machines

None

Patients

should

know

they

react

felodipine before they drive or use machines

because occasionally dizziness or fatigue may

occur.

None.

Pharmacokinetic

properties

Elimination and metabolism: The

average half-life of felodipine in

the terminal phase is 25 hours.

There

significant

accumulation

during

long-term

treatment.

Felodipine

extensively metabolised by the

liver and all identified metabolites

are inactive. Elderly patients and

patients

with

reduced

liver

function have an average higher

plasma

concentration

felodipine than younger patients

Elimination and metabolism: The average half-

life of felodipine in the terminal phase is 25

hours. There is no significant accumulation

during

long-term

treatment.

Felodipine

extensively metabolised in by

the liver

cytochrome

P450

(CYP3A4)

identified

metabolites

inactive.

Elderly

patients and patients with reduced liver function

have an average higher plasma concentration of

felodipine than younger patients

ןולעב ןולעב

ןכרצל ןכרצל

תורמחהה

תושקובמה קרפ

ןולעב טסקט

יחכונ טסקט

שדח תויוותה

ןיא יתמ שמתשהל

?

רישכתב הלחממ

לש

ימותסש

בלה

וא

רירש

בלה

hypertrophic cardiomyopathy

תורהזא תודחוימ תועגונה שומישל

:

הפורתב תופורת

ימסוח

םיזנא

HIV protease

לופיטל(

AIDS

ןוגכ

)ריבנוטיר

,ןיאוטינפ ןוטיברבונפ ,ןיפזמאברק

-היספליפאל( תלחמ

)הליפנה

סומילורקט

שומישל(

רחאל תלתשה

הילכ

וא

.)דבכ ןיצחפמפיר

לופיטל( םוקירפיה )תפחשב

םוטרופרפ

St John’s

Wort

חמצ

יאופר

לופיטל

ןואכידב

.הדרחו םיטרוטיברב

ץנריבפא )העגרהל(

וא

ןיפריבנ לופיטל(

תלחמב

AIDS

ןירפרוו )

לולידל( ןירופסולקיצ ,)םד

רקיע(

שומישה

י"ע ילתשומ

םירבא

םגו

לופיטל

תקלדב

םיקרפמ תינורגש

תלחמו

סיזאירוספ

)}תחפס{

שמתשהל ןיא

ילבמ הפורתב

אפורב ץעוויהל

תלחתה ינפל

:

לופיטה

ןיב תובוגת

:

תויתופורת

יאוול תועפות תועפות

יאוול

תוחיכש

דואמ

תועיפשמ(

לע רתוי

מ

1

ךותמ

10

)םילפוטמ

תוחיפנ

םיילגרב

םיילוסרקבו תועפות

יאוול

יתלב

תוחיכש

תועיפשמ(

לע תוחפ

מ

1

ךותמ

100

)םילפוטמ קפוד

בל

קזח

)היצטיפלפ( ץחל

םד

ךומנ

אטבתמה

תשגרהב

ןופלע

וא תרוחרחס תועפות

יאוול

תורידנ

תועיפשמ(

לע

תוחפ

מ

1

ךותמ

1,000

םישנא

החירפ

םישוגו

רועב תועפות

יאוול

תורידנ

דואמ

תועיפשמ(

לע תוחפ

מ

1

ךותמ

10,000

)םישנא ןתמ

ןתש

םיתיעל

,תופוכת ךרדב

ללכ

ךשמב םויה

:

הקנהו ןוירה

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